During the third trimester of pregnancy, growth of the fetus is greater than at any other time in its development. Of an estimated 4.2 million live births in the United States each year, approximately 383,000 (about 9%) occur prematurely. A low birth-weight infant or any infant born prematurely misses part or all of the critical period of in utero growth, and therefore, would benefit from a nutritional formula that contains greater amounts of nutrients than are found in standard infant formulas or in breast milk in order to support nutrient accretion at the in utero rate leading to growth and development of the infant. Further, a nutritional formula for low birth weight infants must provide these nutrients without disrupting or stressing the physiologic and metabolic systems of the preterm infant that are not yet fully developed.
The most common medical problem encountered in the premature infant is respiratory in origin often due to a lack of pulmonary development. For example, respiratory distress syndrome, aspiration syndromes, and pneumonia frequently occur in the first hours of life. As a consequence, these infants suffer from bloodlung gas exchange disorders which most typically result in a blood level of carbon dioxide which is clinically considered too high and an oxygen level which is considered too low. Aggressive medical intervention is required to treat these infants and includes the administration of supplemental oxygen, endotracheal intubation and mechanical ventilation with positive pressure respirators.
Such aggressive therapy and the underlying diseases themselves result in chronic pulmonary damage which persists beyond the first four weeks of life in approximately 18% of these premature infants. This chronic pulmonary disease, termed bronchopulmonary dysplasia (BPD), is currently the most common and persistent complication of respiratory disease in premature babies and constitutes the majority of infants hospitalized chronically in modern intensive care nuseries.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy and early childhood which is a well-recognized, but poorly defined, clinical entity first described by Northway et al in "Pulmonary Disease Following Respiratory Therapy of Hyaline Membrane Disease", New England Journal of Medicine; 296:357 (1967). This diagnosis is most frequently assigned to infants who are born prematurely, require supplemental oxygen and ventilatory support for respiratory distress syndrome (RDS), and demonstrate clinical and roentgenographic evidence of chronic lung disease at twenty eight to thirty days of life. Four factors are believed to be important in the pathogenesis of this disease: 1) susceptibility of the infant (for example, immature lungs); 2) early acute lung damage; 3) secondary injury by oxidants and/or proteolytic enzymes; and 4) abnormal lung development and/or poor healing.
Structural and biochemical immaturity of the lungs influence the response to and recovery from neonatal lung disease and oxygen therapy. Immaturity of the antioxidant defense systems of the lungs of premature infants may further exacerbate the condition of the compromised lungs and impair the healing process. Surfactant deficiency and/or immaturity result in increased epithelial permeability and increased airway distensibility of the lungs. These factors predispose lung tissue to the development of epithelial necrosis in the small airways.
While barotrauma--induced lesions from oxygen administration by mechanical ventilation--may represent the initial lung injury, development of the more chronic lung condition (BPD) is influenced by secondary injury caused by oxidants and/or proteolytic enzymes. Sources of oxidant injury in addition to therapeutic oxygen include xanthine oxidase-generated radicals and oxygen radicals generated by white blood cells attracted to lung tissue by bacterial infection. Continued therapeutic oxygen administration interferes with lung repair and healing by prolonging interstitial edema and inhibiting DNA synthesis.
Carbon dioxide retention, systemic hypertension, electrolyte derangements, hypercalciuria, osteopenia, a mixed acid-base disorder consisting of chronic respiratory acidoses with compensatory metabolic alkalosis, and hypoproteinemia are representative of the metabolic and nutritional status of the infant with BPD. Failure to grow is often observed in these infants and is of major clinical significance.
Nutritional status is associated with tolerance to hyperoxia and the process of pulmonary repair during the acute phases of neonatal lung disease. Failure to provide adequate energy to an infant having a chronic lung disease has been shown to aggravate the effects of oxygen-induced lung damage. (Roberts, "Implications of Nutrition in Oxygen-Related Pulmonary Disease in the Premature Infant", Advances in Pharmacology Therapy; 8:43 (1978)). However, there is disagreement regarding the potential therapeutic role specific nutrients may have in preventing RDS and/or in ameliorating both the acute phases and the resultant chronic conditions associated with BPD. Vitamin A (retinol), inositol, and a number of other nutrients that have antioxidant effects have received recent interest.
Inositol is a component of cell membrane phospholipids, and compounds containing inositol are important in signal transduction. Inositol influences cellular function and organ maturation. A deficiency of inositol is associated with fatty liver, intestinal lipodystrophy and a lack of infant growth. (M. Hallman et al, New England J. Medicine, Volume 326, pages 1233-1239, 1992). This publication further suggests that parenteral administration of inositol to preterm or low birth weight infants with respiratory problems resulted in: decreased severity of the pulmonary problems; decreased mortality resulting from the respiratory problems; decreased retinopathy and blindness caused by it. It is believed that inositol therapy reduces respiratory problems in preterm infants by acting as a substrate for enhancing the synthesis and secretion of lung surfactant phospholipids. Thus, inositol supplementation during the early neonatal period decreases the likelihood of severe, chronic injury of the retina and lungs of premature infants.
Bronchopulmonary dysplasia (BPD) is characterized by oxygen dependency and radiographic changes in the lungs. Infants diagnosed with BPD frequently exhibit abnormal growth and development in conjunction with markedly elevated blood carbon dioxide levels. In addition, systemic hypertension has been observed in patients with BPD prompting restriction of sodium and fluid intakes to lessen the likelihood of pulmonary edema. Calcium metabolism in these infants is often compromised by the administration of the drugs furosemide or theophylline. These clinical practices may contribute to the osteopenia frequently reported in infants with BPD as well as to the fluid and electrolyte alterations of hypernatremia, hypochloremia, dehydration and/or hypocalcemia. To further complicate the metabolism and homeostasis required for normal growth and development, these infants frequently exhibit acid-base disorders. This is generally a mixed acid-base disorder consisting of chronic respiratory acidosis followed by the compensatory metabolic alkalosis. Further, to avoid potential lung damage during the administration of oxygen in the ventilation process, the biological antioxidant systems of these infants need to be operating at a maximum efficiency. The efficiency of these antioxidant systems can be increased by feeding the infants compositions containing compounds such as vitamin E, selenium, and beta-carotene.
Nutritional support is the primary focus in the management of BPD since the scarred and fibrotic lungs must be provided with the substrates to support healing and to promote infant lung and somatic growth. Numerous clinical investigators have reported increased nutritional requirements for infants with acute or chronic lung problems. Increased oxygen demand is due, in part, to the increased work of breathing and increased demand for cardiac output. Moreover, metabolic demands may result in increased carbon dioxide production which contributes to the excretory load placed on an already compromised lung. As a result of a taxed nutritional status, brain growth may be slighted, lean body mass may be lower than normal, and short stature may ensue.
Thus, it is useful to feed infants with acute or chronic lung disorders a nutritional formula which results in a decreased carbon dioxide production. It is well known that the complete combustion of one mole of carbohydrate produces more carbon dioxide than the complete combustion of one mole of fat relative to the amount of oxygen consumed in in vitro calorimetry studies. This same phenomenon occurs when these fuels are combusted, or oxidized, in the human body. Thus a diet rich in fat and poor in carbohydrate would be expected to result in a lower excretory burden on the lungs than a diet rich in carbohydrate due to the lower carbon dioxide load produced. This in fact has been shown in adults where fat rich and carbohydrate poor diets result in an decreased respiratory quotient and rate of carbon dioxide production. In addition there was also an improvement in pulmonary function in adults fed a high fat diet, as measured by a decrease in minute ventilation, i.e. number of breaths per minute multiplied by total lung volume.
Low birth-weight infants with compromised lung function need to be fed nutritional formulas which not only meet the criteria noted above to support infant growth but which in addition do not cause distress to the immature pulmonary system. However, the nutritional requirements of infants with chronic lung disorders such as BPD are often difficult to meet because of the necessity to restrict fluid intake, poor digestive tolerance of the formula, and/or increased energy demands resulting from the excess work of breathing due to compromised lung function and to repair injured pulmonary tissue. Fluid intake is restricted in an effort to reduce the level of pulmonary edema. Further, the feeding difficulties resulting from chronic respiratory distress or from developmental delay of these infants frequently prevent their consumption of the minimum nutrient intakes of between 130-150 kcal/kg body weight which are known to be required to support adequate growth. In comparison, normal low birth weight infants who do not have compromised lung function require a daily energy intake of only about 120 kcal/kg body weight.
It is clear from the above discussion that there is an urgent medical need for the development of specialized infant nutrient formulas which not only provide the energy, vitamin, mineral and essential elements necessary to support ex utero growth but which also have an increased caloric density in order to accomodate the fluid intake restrictions commonly encountered in the treatment of infants with compromised lung function. Furthermore it is useful to consider feeding such infants a nutritional formula which results in decreased carbon dioxide production. Calorically dense compositions wherein the calories are derived from an increased fat and decreased carbohydrate content as compared to existing prior art infant formulas may achieve this objective. Such compositions, especially when also supplemented with inositol and antioxidants, are useful in the clinical treatment of preterm infants having cardiovascular or chronic lung conditions and also in the treatment of extremely low birth weight infants (i.e. those infants weighing less than 1000 grams at birth). Such an infant formula composition would also serve to overcome problems associated with microbial contamination resulting from physically adding caloric supplements to currently available infant formulas at, or shortly before, the time of feeding of the infant.
The instant Invention meets the nutritional needs of low birth weight and/or premature infants having compromised lung function. The Invention meets these needs by supplying a calorically dense nutritional formula which not only contains all the essential minerals, vitamins and energy requirements to fully support infant growth at the in utero rate but which in addition reduces the physiological stress applied to the underdeveloped organs of the premature infant. The nutritional product of the Invention is substantially more calorically dense than any prior art infant formula compositions and also supplies over 60% of the needed calories in the form of fat thereby decreasing the rate of carbon dioxide production. Further as a consequence of the above, the work of breathing, a measure of pulmonary effort, is also decreased. Also because of the increased caloric density of the formula of the instant Invention, this product is able to deliver appropriate nutrient levels in a diminished volume.